A molecular orbital study of the conformation of barbiturates

The all-valence electrons molecular orbital method PCILO (Perturbative Configuration Interaction using Localized Orbitals) is applied to the study of the conformational and electronic properties of barbiturates. The results indicate the preference for specific conformations which correspond to a tendency for at least a partial folding of the aliphatic substituents towards the barbituric ring, and the eclipsing by the cyclic substituents of the bonds ending at C₅. The theoretical results agree with available experimental data from X-ray crystallography. On the other hand, the substituents at C₅ exert a negligible influence on the charge distribution in the barbituric ring. This situation agrees with the hypothesis that the factors responsible for the pharmacological activity of these drugs reside probably essentially in the electronic properties of the barbituric ring system (perhaps in its ability to hydrogen-bond with adenine), the role of the substituents at C₅ being mainly to favor the transfer of the drug to its receptors and the establishment of an appropriate contact with it.     

A molecular orbital study of the conformation of formycin

Semiempirical quantum mechanical calculations, using the iterative extended Huckel theory, are carried out for the evaluation of conformational energies, dipole moment and net atomic charges as a function of the rotation about the glycosidic bond. Torsion about the C(4′)-C(5′) bond has also been considered. The energy diagrams for either the gg or gt rotamers of formycin predict that neither the first or the second energy minimum fall in the classical anti or syn regions. The predicted energy difference between the two most preferred conformations is rather large (3 kcal/mole). In contrast adenosine is predicted to favor the anti conformation by less than 1 kcal/mole. Barriers to internal counter-clockwise rotation about the glycosidic bond are higher for adenosine.     

A molecular orbital study on the conformation of enniatin B

Molecular orbital calculations using the PCILO method are performed on the conformation of the symmetrical form of enniatin B. The values of the Φ and ψ angles found for the preferred conformation agree closely with the results of X-ray study of the K⁺ complex of enniatin B.     

A molecular mechanics and semiempirical molecular orbital study on the conformation of polynorbornene chains

The conformational analysis of polynorbornene (PNB) chains was investigated with the AM1, MM2, AMBER and OPLS methods taking into consideration the possibility of binding of norbornene monomers to each other at various positions, i.e. exo–exo, exo–endo, endo–endo. The chain that is formed by connecting exo–endo positions of the monomers has lower torsional barrier energy than those formed with bonds at other positions and has more flexibility. It is determined that the thredisyndiotactic chain formed by exo–endo addition adopts a helix structure and has a coil shape. The disyndiotactic chain formed by connecting norbornene monomers in mixed type has a linear structure. It is found that the repeat unit conformations of thredisyndiotactic and disyndiotactic chains of PNB are TGTG^– and (TGTG^–)₂, respectively.     

A molecular orbital study on the enzymic reaction mechanism of alpha-chymotrypsin

On the basis of the three-dimensional structure of the active site of α-chymotrypsin determined by X-ray diffraction analysis, we calculated a total energy and delocalization energy by using a molecular orbital method including all valence electrons, i.e. σ- and π-electrons. The calculated potential curve for a hydrolysis by a-chymotrypsin reproduced the experimental curve well, and the relative magnitudes of all steps in the reaction path explain the experimentally obtained activation energies satisfactorily. The validity of the “charge relay system” proposed by Blow and co-workers was investigated from the quantum-chemical point of view, and the possible importance of this structure for the acceleration of the hydrolysis through a proton transfer within the active site was pointed out. Delocalization energy was proved to play an important role in lowering the activation energy, and the effect of “orbital steering” suggested by Koshland and co-workers was also shown to be of importance for the catalytic reaction of α-chymotrypsin.     

Unfolding pathway of myoglobin: molecular properties of intermediate forms

The guanidine-induced unfolding of myoglobin as well as apomyoglobin has been found to involve the occurrence of at least a molecular intermediate observed at low denaturant concentrations, the molecular properties of which resemble those possessed by the acid-denatured form of the protein. The two partially unfolded forms show the same secondary structure and similar tryptophanyl fluorescence emission and polarization but exhibit marked differences in the tyrosine contributions to the near-ultraviolet circular dichroism and in the degree of solvent accessibility to tyrosyl residues. The molecular characterization of the two structural forms indicates that acids disorganize the 80-146 molecular domain identified in the myoglobin molecule to a great extent with respect to that induced by low guanidine concentration, whereas the structure of the 1-79 domain appears to be quite similar in the two molecular forms.     

A molecular dynamics study on intermediate structures during transition from amorphous to crystalline state

Molecular dynamics (MD) simulations are carried out for model aluminium with 500, 864, 1372 and 2048 atoms interacting with Sutton-Chen version of embedded atom method (SCEAM) based on many body interactions. The systems equilibrated in an FCC structure have, first, been melted and then solidified with specifically selected single cooling rate which forms unstable amorphous state in the system. The local structures of the system have been analysed by bond orientational order parameters to distinguish the simple structures in the systems. The radial distribution functions (RDF) and atomic coordinates have also been analysed for determining the local structural properties. It has been observed that the phase sequences of the systems, except for those of the 2048 atoms, are FCC → Liquid → Amorphous → Mixed Crystal. Types of the crystals in the mixed state depend on the number of the atoms in the system. The final phase of the system with 2048 atoms is amorphous state.     

Comparison of the mutagenic activity of the benzene metabolites, hydroquinone and para-benzoquinone in the supF forward mutation assay: a role for minor DNA adducts formed from hydroquinone in benzene mutagenicity

Benzene, a ubiquitous environmental pollutant and occupational hazardous chemical, is a recognised human leukaemogen and rodent carcinogen. The mechanism by which benzene exerts its carcinogenic effects is to date unknown but it is considered that mutations induced by benzene-DNA adducts may play a role. The benzene metabolite, para-benzoquinone (p-BQ) following reaction in vitro with DNA, forms four major adducts, which include two adducts on 2'-deoxyguanosine 3'-monophosphate (dGp). Reaction of DNA with the benzene metabolite hydroquinone (HQ) results in only one major DNA adduct, which corresponds to one of the dGp adducts formed following reaction with p-BQ. The mutagenicity of the adducts formed from these two benzene metabolites was investigated using the supF forward mutation assay. Metabolite-treated plasmid (pSP189) containing the supF gene was replicated in human Ad293 cells before being screened in indicator bacteria. Treatment with 5-20 mM p-BQ gave a 12 to 40-fold increase in mutation rate compared to 5-20 mM HQ treatment, a result reflected in the level of DNA modification observed (8 to 26-fold increase compared to HQ treatment). Treatment with p-BQ gave equal numbers of GC --> TA transversions and GC --> AT transitions, whereas treatment with HQ gave predominantly GC-->AT transitions. The spectra of mutations achieved for the two individual treatments were shown to be significantly different (P = 0.004). A combination of both treatments also resulted in a high level of GC --> AT transitions and a synergistic increase in the number of multiple mutations, which again predominated as GC --> AT transitions. Sites of mutational hotspots were observed for both individual treatments and one mutational hotspot was observed in the multiple mutations for the combined treatment. These results suggest that the dGp adducts formed from benzene metabolite treatment may play an important role in the mutagenicity and myelotoxicity of benzene.     

A molecular orbital study of stability and the conformation of double-stranded DNA-like polymers

The stacking and hydrogen bonding energies between bases in the B form of DNA were calculated by a perturbation method using the wave functions by the CNDO and the P-P-P methods. The exchange energies were calculated by using the corresponding orbitals. The magnitudes of the sums of the average stacking and hydrogen bonding energies per base pair of double-stranded DNA-like polymers are in good parallel with the melting temperatures of the polymers. The polymers containing I-C pairs are exceptions to this relation. Intrastrand stacking bases have the potential minimum at the distances of 2·8–3·7 Å. The minimum of stacking energy of double-stranded polymer for rotation of base pair around the helix axis exists near 36°. The deviation of the potential minimum from 36° seems to parallel the feature of the X-ray diffraction pattern of the polymer.     

A molecular orbital study of the protein-controlled bathochromic shift in a model of rhodopsin

A molecular orbital study based on the Pariser-Parr-Pople method has been made of the effect of a negative charge on the long wavelength band of the protonated Schiff base of methylamine and retinal. The results show that the energy of the lowest transition, but not the oscillator strength, is highly dependent on the position of the negative charge. With the charge at infinity, the spectral maximum is found to be 524.7 nm. When the charge is moved closer to the Schiff base, the spectrum shows a blue shift from this value toward 440 nm. However, a red shift to about 556 nm is calculated when the charge is moved to the opposite end of the molecule. These results support the theories which hold that the position of a negative charge on the protein controls the observed spectral shifts on rhodopsin formation.     

Palmitoyl-L-carnitine, a metabolic intermediate of the fatty acid incorporation pathway in erythrocyte membrane phospholipids

In this paper we report that palmitoyl-L-carnitine can be a metabolic intermediate of the fatty acid incorporation pathway into erythrocyte membrane phosphatidylcholine, and phosphatidylethanolamine. Phospholipid acylation was evaluated by measuring the incorporation of radioactive [1-14C]-palmitoyl-L-carnitine in membrane erythrocyte ghost phospholipids in the presence or absence of CoA. CoA highly stimulated the incorporation of [1-14C]-palmitic acid into both the phospholipids examined, although the incorporation was also evident in the absence of added CoA. Incorporation of [1-14C]-palmitic acid into phosphatidylcholine was greater than into phosphatidylethanolamine. 2-Bromo-palmitoyl-CoA, an irreversible inhibitor of the erythrocyte carnitine palmitoyltransferase, inhibited the acylation process.     

A molecular orbital study on the oxidation of hydrogen donor molecules by peroxidase compound II

The electronic characteristics of some hydrogen donor substrate (phenol and aniline derivatives) for peroxidase reaction were calculated with the aid of the CNDO/2 and other methods. These results were compared with the experimental data concerning the rate of oxidation of these compounds by peroxidase and hydrogen peroxide. No simple relationship between the total or frontier electron densities on the oxygen or nitrogen atoms, or the lowest unoccupied orbital energies, and the rate of oxidation was found. It was, however, found that the logarithm of the rate of oxidation for the compounds studied correlates linearly with the highest occupied orbital energies. Based on these results, the mechanism of electron transfer from the substrate to compound II is discussed.     

A molecular orbital study on the interaction between the cytochrome P-450 and its substrates.

Models for the interaction of the cytochrome P-450 with its substrates, namely for the type I interaction are proposed in which the molecular planes of the aromatic substrate and the porphyrins of P-450 are in parallel. Optical values such as transition energies and oscillator strengths for the isolated P-450 and P-450-substrate complex are calculated by means of molecular orbital method (ASMO SCF CI method), and they are compared with the observed values. The fact that no appreciable shift in the absorption peak of Soret band of P-450 was observed upon addition of substrate is reflected well in the calculation. Similarly, the well-known fact that the absorbance of the P-450 was decreased by mixing it with the substrate is also explained well by the calculated oscillator strength for the isolated P-450 and the stacked complexes. From the good agreement between the calculated results and the observed ones, it is suggested that the proposed models might be true reflections of the interactions between the P-450 and its substrates.